Method for generating secondary phosphines

ABSTRACT

This invention provides a method for generating secondary phosphines from secondary phosphine oxides in the presence of a reducing agent, such as diisobutylaluminum hydride (DIBAL-H), triisobutyldialuminoxane, triisobutylaluminum, tetraisobutyldialuminoxane, or another reducing agent comprising: (i) an R 1 R 2 AlH moiety, wherein R 1  and R 2  are each an alkyl species or oxygen, and wherein at least one of R 1  or R 2  comprises at least 2 carbon atoms, or (ii) an R 1 R 2 R 3 Al moiety, wherein R 1 , R 2 , and R 3  are not hydrogen, and wherein at least one of R 1 , R 2 , and R 3  is an alkyl species comprising a β-hydrogen, not including triethylaluminum. Preferred reducing agents for the present invention include: diisobutylaluminum hydride, triisobutyldialiuminoxane, triisobutylaluminum, tetraisobutyldialuminoxane, and combinations thereof.

FIELD OF INVENTION

This invention relates to organic compounds and methods for theirpreparation. More specifically, this invention relates to an improvedmethod for the production of secondary phosphines using a reducing agentcomprising a tri-coordinate aluminum moiety. In particular, thisinvention relates to a method for the reduction of secondary phosphineoxides to secondary phosphines using a reducing agent comprising atri-coordinate aluminum moiety.

BACKGROUND OF THE INVENTION

Most ligands for asymmetric catalysis contain phosphines, including thephosphinoimidazolines found, for example, in U.S. Pat. No. 6,316,620. Acommon method for construction of these phosphine ligands involvescoupling with a secondary phosphine, R₂PH.

A fundamental physical property of secondary phosphines is their extremeair sensitivity. Most secondary phosphines will completely oxidize inair within a few minutes to typically undesired secondary phosphineoxides. Because of this problem, there is a long-felt need for improvedsynthetic procedures for the preparation of secondary phosphinesemploying a minimum number of synthetic steps and that minimize physicalmanipulations that may increase the possibility of contact with air.Unfortunately, the prior art methods for preparation of these speciessuffer from numerous deficiencies.

One prior art method for the preparation of secondary phosphines, whichhas been proposed to reduce inadvertent oxidation, employs BH₃ complexes(Stankevi{hacek over (c)}, M.; Pietrusiewicz, K. M. Synlett 2003, 7,1012-1016). Unfortunately, in practice, this method has been found togenerate undesirable byproducts. Further, there are severe hazardsassociated with handling BH₃ (Reisch, M. Chem. Eng. News 2002, 80 (26),7).

Another method available for producing secondary phosphines employslithium aluminum hydride (LAH) (Kapoor, P. N.; Venanzi L. M. Helv. Chim.Acta 1977, 60 (277), 2824-2829). The problem with LAH is that it is alsoa very hazardous substance to handle. Moreover, in practice, LAH has notbeen found useful for producing those phosphine ligands that are ofparticular interest in the art, such as the phosphinoimidazolines.

The reduction of secondary phosphine oxides to secondary phosphines hasbeen accomplished with diphenylsilane (McKinstry, L.; Livinghouse T.Tetrahedron 1994, 50 (21), 6145-6154). Unfortunately, this methodrequires very high temperatures (i.e., greater than 200° C.). Anothermethod of reducing secondary phosphine oxides uses a combination oftrichlorosilane (Cl₃SiH) and triethylamine (Elding, L. I.; Kellenberger,B.; Venanzi, L. M. Helv. Chim. Acta 1983, 66 (6), 1676). However, asignificant problem with this method is that trichlorosilane is acorrosive reagent, whose extremely low boiling point (31° C.) and lowflash point (−13° C.) make it completely unsuitable for typical plantoperations.

One of the most common methods for synthesis of secondary phosphineoxides used in industry is a two step process in which an intermediatesecondary chlorophosphine is produced (Casalnuovo, A. L; RajanBabu T.V.; Ayers, T. A.; Warren, T. H. J. Am. Chem. Soc. 1994, 116 (22), 9869).A chlorophosphine, an air-sensitive and water-sensitive compound, isfirst prepared and then isolated. This is carried out with phosphoroustrichloride (PCl₃), which is a corrosive reagent. High vacuum isemployed to fully remove the by-products of this reaction. Thechlorophosphine must then be reduced, usually, by LAH, with the hazardsassociated with using that reagent.

Therefore, there is a need for an improved method for generatingsecondary phosphines in high yield and purity, without the need toemploy hazardous materials.

In U.S. Pat. No. 4,113,783 to Malpass et al., which corresponds to GreatBritain Patent No. 1,520,237 to Texas Alkyls, there is described the useof DIBAL-H for the reduction of a tertiary phosphine oxide,triphenylphosphine oxide, to a tertiary phosphine, triphenylphosphine.The patent is specifically directed to triphenylphosphine oxide. Noother tertiary phosphine oxides are cited. There is no suggestion forapplication of DIBAL-H with respect to the reduction of secondaryphosphine oxides. Therefore, the usefulness of DIBAL-H in the reductionof secondary phosphine by the present inventor was entirely unexpected.

SUMMARY OF THE INVENTION

This invention provides a method for generating secondary phosphinesfrom secondary phosphine oxides in the presence of a reducing agent,such as diisobutylaluminum hydride (DIBAL-H), triisobutyldialuminoxane,triisobutylaluminum, tetraisobutyldialuminoxane, or another reducingagent comprising: (i) an R₁R₂AlH moiety, wherein R₁ and R₂ are each analkyl species or oxygen, and wherein at least one of R₁ or R₂ comprisesat least 2 carbon atoms, or (ii) an R₁R₂R₃Al moiety, wherein R₁, R₂, andR₃ are not hydrogen, and wherein at least one of R₁, R₂, and R₃ is analkyl species comprising a β-hydrogen, not including triethylaluminum.

Preferred reducing agents for the present invention include:diisobutylaluminum hydride, triisobutyldialiuminoxane,triisobutylaluminum, tetraisobutyldialuminoxane, and combinationsthereof.

DETAILED DESCRIPTION OF THE INVENTION

The preferred solution to the aforementioned problems of spontaneousoxidation and accompanying hazards in the production of phosphineligands is to use an alkyl-substituted, tri-coordinate aluminum species,such as diisobutylaluminum hydride (DIBAL-H), in order to reducesecondary phosphine oxides to secondary phosphines. Thealkyl-substituted, tri-coordinate aluminum species of the presentinvention are referred to herein as “reducing agents.” Traditionallydefined, a reducing agent according to the present invention donateselectrons to the secondary phosphine oxide, such that the oxygen isremoved therefrom. Nonetheless, it is surprisingly notable that apreferred reducing agent of the present invention, i.e., DIBAL-H, isalso traditionally defined as a Lewis acid. Moreover, the reducingagents of the present invention are also referred to herein as“organometallic.” Compounds that are organometallic comprise ametal-carbon bond.

The organometallic reducing agents according to the present inventionmay be dialkyl species (i.e., two alkyl groups bonded with the metalatom) or trialkyl species (i.e., three alkyl groups bonded with themetal atom). As used herein, “alkyl” refers to groups comprisingbranched or unbranched hydrocarbons, which may be unsubstituted orsubstituted. Dialkyl species are more preferred in comparison totrialkyl species.

Whether a particular organometallic reducing agent according to thepresent invention is a dialkyl or trialkyl species, at least one alkylgroup thereof must comprise at least 2 carbon atoms. In light of thisattribute of the reducing agents, while not being limited to aparticular reaction mechanism, it is believed that a β-hydrideelimination event occurs in reduction reactions created by reducingagents of the present invention that do not comprise an aluminum hydride(AlH) moiety. For those reducing agents that do comprise an aluminumhydride moiety, it is possible that the reduction reaction will go tocompletion without a β-hydride elimination event, especially when thereduction reaction uses an excess of the AlH-containing reducing agent.Triethylaluminum is explicitly excluded from the present inventionbecause it is not a reducing agent (Zhurnal Obshchei Khimii 1992, 62(5),1027).

Therefore, the present invention is directed to a reducing agentcomprising: (i) an R₁R₂AlH moiety, wherein R₁ and R₂ are each an alkylspecies or oxygen, and wherein at least one of R₁ or R₂ comprises atleast 2 carbon atoms, and/or (ii) R₁R₂R₃Al moiety, wherein R₁, R₂, andR₃ are not hydrogen, and wherein at least one of R₁, R₂, and R₃ is analkyl species comprising a β-hydrogen, not including triethylaluminum.

Examples of dialkyl aluminum species contemplated by the presentinvention include: diethylaluminum chloride, diisobutylaluminumchloride, disecbutylaluminum choride, diethylaluminum hydride,diisobutylaluminum hydride, and disecbutylaluminum hydride, andtriisobutylaluminoxane.

Dialkyl species of the organometallic reducing agents of the presentinvention may comprise any suitable ion, such as a chloride or hydrideion. A preferred dialkyl species for the organometallic reducing agentsof the present invention comprises a hydride ion.

Examples of trialkyl aluminum species contemplated by the presentinvention include: tri-n-butylaluminum, tri-iso-butylaluminum,tri-sec-butylaluminum, trihexylaluminum, tri-n-octylaluminum,

Further suitable aluminum species for use in the present inventioninclude higher molecular weight trialkylaluminums, i.e., substitutedwith C₂-C₂₀ alkyl groups, such as trioctylaluminum,trioctadecylaluminum, and tridocosylaluminum.

DIBAL-H, a preferred reducing agent according to the present invention,is a very robust and safe reducing agent that has been used extensivelyin plant operations. It is not a hazardous reducing agent like LAH orborane. It is inexpensive, and can be purchased commercially in bulk inneat form. DIBAL-H may be dispensed in process-safe solvents, such astetrahydrofuran (THF), toluene, and heptane, which do not have the lowboiling point and flash point problems associated with Cl₃SiH.Unexpectedly, it has been found that DIBAL-H reduction of secondaryphosphine oxides may be effectuated between ambient temperature (e.g.,room temperature) and the reflux temperature of THF (67° C.),particularly when the secondary phosphine oxide does not compriseselectron withdrawning substituents. Therefore, high temperatures, suchas those required for phenylsilane, are not needed with the DIBAL-Hreduction method of the present invention. Alternatively, particularlywhen the secondary phosphine oxide does comprise electron withdrawingsubstituents, the reduction may be effectuated below ambienttemperature.

As compared to a commonly used prior art process for reducing secondaryphosphine oxides using LAH, wherein a 1:1 mixture of the desiredsecondary phosphine is formed with the unwanted primary phosphine,reduction with a reducing agent of the present invention (e.g., DIBAL-H)causes no primary phosphine to be formed as illustrated below.

As exemplified by reference to DIBAL-H, reduction reactions of thepresent invention creates a more pure product in a single reaction step.This is also evident when reduction reactions using organometallicreducing agents of the present invention, e.g., DIBAL-H, are compared toreduction reactions using borane, wherein the latter method formssignificant amounts of unwanted hydroxyphosphines.

Since secondary phosphines are known to be extremely air-sensitive, mostconventional purification methods cannot be used. Distillation is thepurification method used in the art. Many substituted secondaryphosphines have extremely high boiling points—in fact, many are solidsat ambient temperature. The high boiling points and the difficultiesassociated with achieving very high vacuum in a plant setting combine tomake purification by distillation very difficult if not impossible toapply productively and safely. The present method provides secondaryphosphines of high purity so that further purification is unnecessary.

One embodiment of the invention provides a substantially anaerobicenvironment for the production of secondary phosphine comprising areaction of a secondary phosphine oxide or mixture thereof with aDIBAL-H/solvent mixture, followed by neutralization and filtration ofthe product-containing organic phase to yield a phosphine product ofhigh purity. An advantageous reflux process may comprise a temperaturerange from ambient temperature, such as room temperature, to atemperature not exceeding the solvent boiling point. Another embodimentof the invention provides a method comprising the steps of adding asecondary phosphine oxide to a pre-heated DIBAL-H and tetrahydrofuranmixture under inert, anaerobic gas pressure, refluxing the reactionmixture to completion, cooling the same to a suitable (e.g., ambient orslightly below ambient) temperature, and quenching the same byneutralization with an aqueous hydroxide reagent. In yet anotherembodiment of the invention, neat DIBAL-H without an organic solvent iscombined with the secondary phosphine oxide.

Non-limiting examples of the present reduction method for makingsecondary phosphines by employment of DIBAL-H, triisobutyldialuminoxane,triisobutylaluminum, and tetraisobutyldialuminoxane is set forth below.

EXAMPLE 1 Production of Bis-(3-Fluorophenyl) Phosphine by Reduction withDIBAL-H

A 2-neck 100 mL flask with a Vigreux condenser was evacuated/Ar filled(3×), then charged with 6.00 mL 1M DIBAL-H/THF (6.00 mmol, 3 eq.), thenheated to 65° C. under N₂. To the warm solution, 476 mg bis(3-fluorophenyl)-phosphine oxide (2.00 mmol, 1 eq.) in 4.0 mL THF wasadded in drops from a syringe over 15 minutes, with caution taken forgas evolution. After one hour at reflux, TLC of a quenched aliquotshowed the reaction was complete to a non-polar product. The mixture wascooled to ambient temperature, and then cautiously quenched by the slowaddition of 10 mL 5% aqueous NaOH. The mixture was stirred vigorouslyfor 10 minutes, then 10 mL of 1:1 MTBE:Hexane was added, and the mixturewas again stirred vigorously for 10 minutes. After stirring was stopped,the phases were allowed to separate, and the upper organic phase wastransferred, via canula, under N₂ pressure, to an air-free filter funnelcontaining MgSO₄, which was attached directly to a 2-neck pear shapedflask as receiver. When the filtration was complete, an N₂ line wasinserted in the side neck of the pear flask, and the solvents wereremoved by evaporation over one hour. The product collected in the baseof the pear flask: 400 mg (89%), as a colorless oil. ³¹P NMR showed thedesired secondary phosphine. ³¹P NMR (CDCl₃, 162 MHz): δ=−41.39 ppm, d,¹J_(PH)=220 Hz.

EXAMPLE 2 Production of Pheylisopropyl Phosphine by Reduction withTriisobutyldialuminoxane

A flask was charged with 2.0 mL 0.36M triisobutyldialuminoxane/toluenesolution (0.72 mmol, 2 eq.), then cooled to −78° C. under Ar. To thiscold solution was then added a solution of 60 mgphenylisopropylphosphine oxide (0.36 mmol, 1 eq.) in 0.75 mL ⁸d THF. Gasevolution was observed. The flask was then allowed to warm to 25° C.After 2 h at 25° C., ³¹P NMR of an aliquot showed the reaction wasalready 50% complete to the desired secondary phosphine, phenylisopropylphosphine, with ³¹P NMR δ=−27.4 ppm.

EXAMPLE 3 Production of Pheylisopropyl Phosphine by Reduction withTriisobutylaluminum

A screw-cap NMR tube was charged with 0.50 mL 1M i-Bu₃Al/Hexane solution(0.50 mmol, 1 eq.), then cooled to −78° C. under Ar. To this coldsolution was then added a solution of 84 mg Phenylisopropylphosphineoxide (0.50 mmol, 1 eq.) in 0.15 mL ⁸d THF. Gas evolution was observed.The tube was then allowed to warm to 25° C. After only 15 min. at 25°C., ³¹P NMR showed the reaction was already 70% complete to the desiredsecondary phosphine, phenylisopropyl phosphine, with ³¹P NMR δ=−27.4ppm.

EXAMPLE 4 Production of Pheylisopropyl Phosphine by Reduction withTetraisobutyldialuminoxane

A screw-cap NMR tube was charged with 0.50 mL 0.29Mtetraisobutyldialuminoxane/toluene solution (0.145 mmol, 1 eq.). To thissolution was then added a solution of 24.4 mg phenylisopropylphosphineoxide (0.145 mmol, 1 eq.) in 0.25 mL ⁸d THF. A small amount of gasevolution was observed. After only 1 hour at 25° C., 31P NMR showed themajor product present was the desired secondary phosphine,Phenylisopropyl phosphine, with ³¹P NMR δ=−27.4 ppm.

EXAMPLE 5 Production of Other Secondary Phosphines by Reduction withDIBAL-H

Similar to the method of Example 1, a large number of secondaryphosphine compounds were obtained by conversion from secondary phosphineoxides. (See Table 1).

The reductions in Table 1 are in THF with 3 equivalents of DIBAL-Hunless otherwise noted.

TABLE 1

Time (min.)/ R₁ R₂ Temp. (° C.) Yield (%) ³¹P NMR C₆H₅ C₆H₅  10/25 86 δ= −44.35, J_(PH) = 218 Hz 4-F-C₆H₄ 4-F-C₆H₄  10/25 90 δ = −44.30, J_(PH)= 216 Hz 4-Cl-C₆H₄ 4-Cl-C₆H₄  10/25 or 83 δ = −45.63, J_(PH) = 219 Hz180/−25 4-CF₃-C₆H₄ 4-CF₃-C₆H₄ 180/−78 79 δ = −41.35, J_(PH) = 221 Hz4-Me-C₆H₄ 4-Me-C₆H₄  10/25 83 δ = −44.66, J_(PH) = 214 Hz 3-F-C₆H₄3-F-C₆H₄  60/−20 89 δ = −41.39, J_(PH) = 220 Hz 3-Cl-C₆H₄ 3-Cl-C₆H₄ 60/−20 81 δ = −40.29, J_(PH) = 219 Hz 3-F, 3-F,  60/−20 82 δ = −39.66,J_(PH) = 219 Hz 5-Me-C₆H₃ 5-Me-C₆H₃ 3,5-F₂, 3,5-F₂,  60/−20 90 δ =−40.03, J_(PH) = 220 Hz 4-OMe-C₆H₂ 4-OMe-C₆H₂ 3,5-Cl₂-C₆H₃ 3,5-Cl₂-C₆H₃ 60/−20 or 90 δ = −39.23, J_(PH) = 221 Hz 180/−25 3,5-F₂-C₆H₃3,5-F₂-C₆H₃  60/−20 or 80 δ = −37.80, J_(PH) = 220 Hz 180/−25 3,5-(CF₃)₂3,5-(CF₃)₂-  60/−20 72 δ = −41.06, J_(PH) = 224 Hz C₆H₃ C₆H₃ 4-OMe-C₆H₄4-OMe-C₆H₄  10/25 91 δ = −43.94, J_(PH) = 214 Hz 4-NMe₂-C₆H₄ 4-NMe₂-C₆H₄ 10/25 92 δ = −45.82, J_(PH) = 211 Hz 2,4,6-Me₃- 2,4,6-Me₃- 180/25 30 δ= −96.23, J_(PH) = 230 Hz C₆H₂ C₆H₂ 2-Naph 2-Naph  10/25 84 δ = −39.96,J_(PH) = 216 Hz 3,5-Me₂-C₆H₃ 3,5-Me₂-C₆H₃  60/25 90 δ = −39.84, J_(PH) =214 Hz Ph C₆H₁₁ 240/50 93 δ = −30.4, J_(PH) = 206 Hz C₆H₅ i-Pr  10/25 90δ = −27.71, J_(PH) = 200 Hz C₆H₅ t-Bu 240/50 86 δ = −8.1, J_(PH) = 227Hz n-Bu n-Bu  60/25 85 δ = −71.34, J_(PH) = 190 Hz C₆H₁₁ C₆H₁₁ 240/50 88δ = −27.93, J_(PH) = 191 Hz t-Bu t-Bu 240/50 87 δ = −20.01, J_(PH) = 198Hz

Preferably, the molar ratio of the tri-coordinate aluminum moiety, i.e.,R₁R₂AlH or R₁R₂R₃Al, to the secondary phosphine oxide is about 1:3 toabout 10:1. Ideally, in reference to the molar ration of 1:3, a reducingagent having a single, tri-alkyl aluminum moiety comprising threeβ-hydrogen atoms, e.g., trialkylaluminum, may be able to reduce threesecondary phosphine oxides. Practically, the molar ratio could be closerto 10:1. It may be preferable to provide an excess of reducing agent tobetter ensure that the reduction of the secondary phosphine oxides goesto completion.

Many suitable reducing agents for the present invention are liquidwithin a temperature range that is useful for effectuating a reactionwith secondary phosphine oxides. When a given reducing agent is liquidat the desired reaction temperature, the given reducing agent may beused neat, i.e., without a solvent.

Alternatively, the reducing agent may be in a mixture with a solvent.The solvent may be selected from hydrocarbons, ethers, and halocarbons.For example, the solvent may be selected from the group consisting of:tetrahydrofuran, toluene, dioxane, xylene, hexane, heptane, cyclohexane,and other hydrocarbons, diethyl ether, and other dialkyl ethers,dichloromethane, dichloroethane, 2-methyl-THF, MTBE, monoglyme, diglyme,triglyme, tetraglyme, chloroform, methylcyclohexane, octane,di-n-butylether, diisopropylether, ethylbenzene, cyclopentylmethylether,and combinations and mixtures thereof. The secondary phosphine productmay be isolated by any suitable means, such as by purification bypartition separation from a mixture of an aqueous and an organicsolvent. Likewise, the secondary phosphine product may be de-watered ordried by any suitable means, such as by distillation of an aqueoussolvent. In a preferred embodiment the reduction reaction may be carriedout anaerobically, for example, by replacing air with inert gas, such asargon and/or nitrogen. When a solvent is preset, the aluminumhydride-solvent mixture comprises a molar ration ranging from 1:20 to20:1.

A significant advantage of the present invention is that the step ofreacting the secondary phosphine with the reducing agent may beeffectuated in a broad temperature range. Using the reducing agent andmethod of the present invention, it is possible to effectuate quickreduction reactions by using a high average temperature, controlledreduction reactions by using a low average temperature, or balancedreduction reactions by using an intermediate average temperature. Giventhe appropriate amount of time, intermediate or low average temperatureis preferred. For the present invention, a high average temperature isan average temperature above about 50° C., a low average temperature isan average temperature below about −25° C., and an intermediate averagetemperature is a temperature between about −25° C. and about 50° C.Depending on the specific way in which the temperature of a particularreaction fluctuates over time, “average temperature” may be the meantemperature or the median temperature. For example, if a particularreduction reaction included a very brief, very large temperaturedeviation, but was very temperature stable otherwise, the averagetemperature for the particular reduction reaction may, more accurately,be defined as the median temperature, instead of the mean temperature,which would be inaccurately skewed.

For very electron-deficient secondary phosphine oxides, such as atetrafluoro derivative, the reduction may be advantageously carried outat a low average temperature. In the absence of electron-withdrawinggroups, a high average temperature may be required to effect thereduction. The method may be less efficient with very electron-richphosphine oxides. In determining optimal reaction temperatures, anevaluation of the electronic nature of the secondary phosphine oxideshould be taken into account.

In light of the fact that excess reducing agent is preferably used tobetter ensure complete reduction of the secondary phosphine oxide, aquenching agent is preferable used to neutralize any un-reacted reducingagent after the reduction reaction is finished. When used, the quenchingagent is preferably an aqueous base in a concentration rangeapproximately from about 10% to about 25%. The concentration of anaqueous base used for the quench could range approximately from 1%-50%.However, a value in the middle of this range is likely to be moreproductive, as, on the one hand, lower concentrations of this aqueousquencher may lead to more insoluble aluminum salts, while, on the otherhand, higher concentrations may lead to product decomposition. A lowconcentration of the aqueous base may be used, as described in Example 1hereinabove, wherein the concentration of the aqueous base NaOH was 5%.A high concentration of the aqueous base may also be used. A practicalupper limited for the concentration of aqueous base is about 50%.

Moreover, the invention may also be practiced by quenching with aminimal amount of water rather than the excess water described inExample 1. However, this modification may generate insoluble materials,which are more difficult to separate from the product. It has been foundthat quenching DIBAL-H generates aluminum salts that are more soluble atbasic pH than at neutral pH.

Preferably, the secondary phosphine is isolated from any water and/oraqueous reaction component. For example, after quenching with an aqueousbase, the reaction mixture may be allowed to separate into an organicphase and an aqueous phase, which may be subsequently removed by anysuitable means, such as drawing off the aqueous phase or evaporating thewater. As would be understood by one of ordinary skill in the art,rather than removing the upper organic phase as described in Example 1,the lower aqueous phase may first be dropped to a second vessel (andre-extracted with an organic solvent, if necessary), and the originalorganic phase dropped to a third vessel for product isolation. If achlorinated solvent such as dichloromethane (CH₂Cl₂) were used in theseparation, the denser organic phase would be on the bottom, and theaqueous phase on the top. In this scheme, it may be advantageous to dropthe lower organic phase through the bottom valve to a second vessel, andthen (if desired) re-extract the remaining aqueous phase with CH₂Cl₂ torecover more product.

Furthermore, the organic solution containing the secondary phosphine mayoptionally be passed through a drying agent in an air-free filter. Onemay also use drying agents, such as sodium sulfate (Na₂SO₄), molecularsieves, silica gel, alumina, and the like. Silica gel and alumina mayhave an added benefit in that any polar impurities in the crude productsolution would be removed in this manner.

When neutralized by a quenching agent, the reducing agent becomesaluminum by-product, which may be separated from the secondaryphosphine. Separating aluminum by-product from the secondary phosphinemay be considered separately from separating water from the secondaryphosphine. For example, if the water is separated byevaporation/distillation, the aluminum by-product initially present inthe aqueous phase may become a precipitate, which may be filtered fromthe organic phase containing the secondary phosphine.

After the water and aluminum by-product have been removed, the secondaryphosphine may be isolated from the organic phase by any suitable means.Alternatively, it is possible to leave the secondary phosphine is theorganic phase and/or with the aluminum by-product. If the secondaryphosphine is not separated from the organic phase and/or the aluminumby-product, it is, nonetheless, most practical to isolate the secondaryphosphine from water.

Although the inventive method is described in the context of synthesisof certain ligands as would be understood by the skilled artisan readingthis disclosure, a large number of ligands formed by coupling withsecondary phosphines may be synthesized.

1. A method for generating a secondary phosphine from a secondaryphosphine oxide comprising a reaction of the secondary phosphine oxideand a reducing agent comprising an R₁R₂AlH moiety, wherein R₁ and R₂ areeach an alkyl species or oxygen, and wherein at least one of R₁ or R₂comprises at least 2 carbon atoms, wherein the secondary phosphine oxideis reacted with the reducing agent in a mixture comprising a solventselected from the group consisting of: hydrocarbons, ethers,halocarbons, tetrahydrofuran, toluene, dioxane, xylene, hexane, heptane,cyclohexane, diethyl ether, dichloromethane, dichloroethane,2-methyl-THF, MTBE, monoglyme, diglyme, triglyme, tetraglyme,chloroform, methylcyclohexane, octane, di-n-butylether,diisopropylether, ethylbenzene, cyclopentylmethylether, and combinationsand mixtures thereof.
 2. A method for generating a secondary phosphinefrom a secondary phosphine oxide comprising a reaction of the secondaryphosphine oxide and a reducing agent comprisina an R₁R₂AlH moiety,wherein R₁ and R₂ are each an alkyl species or oxygen, and wherein atleast one of R₁ or R₂ comprises at least 2 carbon atoms, furthercomprising the steps of: providing a quenching agent adapted to generatea neutralized aluminum by-product from the reducing agent that remainsafter the reaction of the secondary phosphine oxide and the reducingagent; isolating the secondary phosphine from (i) the neutralizedaluminum by-product and (ii) water.
 3. The method of claim 2, whereinthe quenching agent is an aqueous base in a concentration rangeapproximately from 10% to 25%.
 4. A method for generating a secondaryphosphine from a secondary phosphine oxide comprisina a reaction of thesecondary phosphine oxide and a reducing agent comprising an R₁R₂AlHmoiety, wherein R₁ and R₂ are each an alkyl species or oxygen, andwherein at least one of R₁ or R₂ comprises at least 2 carbon atoms,wherein the step of reacting the secondary phosphine oxide with thereducing agent is anaerobic.
 5. A method for generating a secondaryphosphine from a secondary phosphine oxide comprising a reaction of thesecondary phosphine oxide and a reducing agent comprising an R₁R₂AlHmoiety, wherein R₁ and R₂ are each an alkyl species or oxygen, andwherein at least one of R₁ or R₂ comprises at least 2 carbon atoms,wherein the step of reacting the secondary phosphine oxide with thereducing agent is effectuated between about −25° C. to 50° C.
 6. Amethod for generating a secondary phosphine from a secondary phosphineoxide comprising a reaction of the secondary phosphine oxide and areducing agent comprising an R₁R₂AlH moiety, wherein R₁ and R₂are eachan alkyl species or oxygen, and wherein at least one of R₁ or R₂comprises at least 2 carbon atoms, wherein the step of reacting thesecondary phosphine oxide with the reducing agent is effectuated at orbelow about −25° C.
 7. A method for generating a secondary phosphinefrom a secondary phosphine oxide comprising the step of reacting thesecondary phosphine oxide with a reducing agent comprising an R₁R₂R₃Almoiety, wherein R₁, R₂, and R₃ are not hydrogen, and wherein at leastone of R₁, R₂, and R₃ is an alkyl species comprising a β-hydrogen atom,not including triethylaluminum, wherein the secondary phosphine oxide isreacted with the reducing agent in a mixture comprising a solventselected from the group consisting of: hydrocarbons, ethers,halocarbons, tetrahydrofuran, toluene, dioxane, xylene, hexane, heptane,cyclohexane, diethyl ether, dichloromethane, dichloroethane,2-methyl-THF, MTBE, monoglyme, diglyme, triglyme, tetraglyme,chloroform, methylcyclohexane, octane, di-n-butylether,diisopropylether, ethylbenzene, cyclopentylmethylether, and combinationsand mixtures thereof.
 8. A method for generating a secondary phosphinefrom a secondary phosphine oxide comprising the step of reacting thesecondary phosphine oxide with a reducing agent comprising an R₁R₂R₃Almoiety, wherein R₁, R₂, and R₃ are not hydrogen, and wherein at leastone of R₁, R₂, and R₃ is an alkyl species cormprising a β-hydrogen atom,not including triethylaluminum, further comprising the steps of:providing a quenching agent adapted to generate a neutralized aluminumby-product from the reducing agent that remains after the reaction ofthe secondary phosphine oxide and the reducing agent; isolating thesecondary phosphine from (i) the neutralized aluminum by-product and(ii) water.
 9. The method of claim 8, wherein the quenching agent is anaqueous base in a concentration range approximately from 10% to 25%. 10.A method for generating a secondary phosphine from a secondary phosphineoxide comprising the step of reacting the secondary phosphine oxide witha reducing agent comprising an R₁R₂R₃Al moiety, wherein R₁,R₂, and R₃are not hydrogen, and wherein at least one of R₁, and R₂, and R₃ is analkyl species comprising a β-hydrogen atom, not includingtriethylaluminum, wherein the step of reacting the secondary phosphineoxide with the reducing agent is anaerobic.
 11. A method for generatinga secondary phosphine from a secondary phosphine oxide comprising thestep of reacting the secondary phosphine oxide with a reducing agentcormprising an R₁R₂R₃Al moiety. wherein R₁, R₂, and R₃ are not hydrogen,and wherein at least one of R₁, R₂, and R₃ is an alkyl speciescomprising a β-hydrogen atom, not including triethylaluminum, whereinthe step of reacting the secondary phosphine oxide with the reducingagent is effectuated between about −25° C. to 50° C.
 12. A method forgenerating a secondary phosphine from a secondary phosphine oxidecomprising the step of reacting the secondary phosphine oxide with areducing agent comprising an R₁R₂R₃Al moiety, wherein R₁, R₂, and R₃ arenot hydrogen, and wherein at least one of R₁, R₂, and R₃ is an alkylspecies comprising a β-hydrogen atom, not including triethylaluminum,wherein the step of reacting the secondary phosphine oxide with thereducing agent is effectuated at or below about −25° C.